P968: ADDITION OF IXAZOMIB TO POMALIDOMIDE AND DEXAMETHASONE IMPROVES PROGRESSION-FREE SURVIVAL FOR MULTIPLE MYELOMA PATIENTS PROGRESSING ON LENALIDOMIDE AS PART OF 1ST LINE THERAPY: ALLIANCE A061202
Authors: P. Voorhees, V. Suman, Y. Efebera, N. Raje, S. Tuchman, C. Rodriguez, K. Santo, M. Bova-Solem, D. Carlisle, U. Saad, P. McCarthy, P. Richardson
Journal: HemaSphere (2022)

Background: Lenalidomide (LEN) maintenance and continuous LEN-based induction therapy until disease progression have become standard of care for frontline therapy of multiple myeloma (MM). As such, an increasing number of patients (pts) in need of 2nd line therapy have LEN-refractory disease. Optimal treatment in this setting has not been rigorously assessed in randomized studies. The phase I portion of Alliance A061202 demonstrated the safety of the ixazomib-pomalidomide-dexamethasone (IXA-POM-DEX) combination for the treatment of pts with LEN and proteasome inhibitor (PI)-refractory MM. Aims: In the randomized phase II portion, we evaluated the addition of IXA to POM-DEX for PI naïve / sensitive pts progressing on LEN as part of 1st line therapy. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), depth of response, survival and safety. Methods: Pts were randomized 1:1 to IXA-POM-DEX or POM-DEX and stratified by prior bortezomib exposure, International Staging System stage (1 and 2 vs 3) and the presence of high-risk cytogenetics. POM was administered at 4 mg on days 1 – 21; IXA 4 mg on days 1, 8 and 15; and DEX 20 mg (>75 years (yrs)) or 40 mg (≤75 yrs) on days 1, 8, 15 and 22 of a 28-day cycle. Treatment was continued until disease progression, the emergence of unacceptable side effects or withdrawal of treatment consent. Results: 38 and 39 eligible pts were assigned to IXA-POM-DEX and POM-DEX, respectively. The median age was 66 yrs (range 41 – 83) and 64 yrs (range 52 – 85). A planned first interim analysis was conducted after 43 out of 57 required events had occurred. PFS favored the IXA-POM-DEX arm (one-sided log rank test value = 4.6345, p=0.03134 [< p-value boundary of 0.058]), yielding a hazard ratio of 0.528 (upper 90% bound = 0.777). A stratified log-rank test found that PFS was superior for the triplet after adjusting for stratification factors (one-sided stratified log rank test value = 5.8371; p=0.0157), adjusted hazard ratio 0.451 (upper 90% bound = 0.694). The ORR favored IXA-POM-DEX (63.2% vs 43.6%, p=0.0853), and the ≥very good partial response was 26.3% vs 5.1%, respectively (p=0.01). The clinical benefit rate (ORR + minimal response rate) was 73.7% and 56.4%. The most common grade 3/4 adverse events included lymphopenia, neutropenia, anemia, and fatigue in 40%, 37%, 16% and 16% of IXA-POM-DEX-treated pts and 26%, 21%, 13%, and 15% of POM-DEX-treated pts. Therapy was discontinued for disease progression in 47.4% of pts on IXA-POM-DEX and 76.9% of pts on POM-DEX and for adverse events in 7.9% and 7.7% of pts, respectively. Summary/Conclusion: The addition of IXA to the POM-DEX backbone improved the depth of response and PFS for pts relapsing on LEN as part of 1st line therapy. Hematologic toxicity was increased with the addition of IXA, but side effects were manageable. The ease of administration of this all-oral combination allowed for safer, uninterrupted treatment during the COVID pandemic. Our results should be confirmed in phase III trials but lend support for this regimen as part of 2nd line therapy for this patient population.